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The Journal of Neuroscience, May 19, 2004, 24(20):4875-4883; doi:10.1523/JNEUROSCI.5584-03.2004

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Development/Plasticity/Repair
Infection with an Endemic Human Herpesvirus Disrupts Critical Glial Precursor Cell Properties

Joerg Dietrich,¹ Benjamin M. Blumberg,² Mikhail Roshal,⁴ Jeffrey V. Baker,² Sean D. Hurley,³ Margot Mayer-Pröschel,¹ and David J. Mock²

Departments of ¹Biomedical Genetics, ²Neurology, ³Anatomy and Cell Biology, and ⁴Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642

Human herpesvirus 6 (HHV-6), a common resident virus of the human CNS, has been implicated in both acute and chronic inflammatory–demyelinating diseases. Although HHV-6 persists within the human CNS and has been described to infect mature oligodendrocytes, nothing is known about the susceptibility of glial precursors, the ancestors of myelin-producing oligodendrocytes, to viral infection.

We show that HHV-6 infects human glial precursor cells in vitro. Active infection was demonstrated by both electron microscopy and expression of viral gene transcripts and proteins, with subsequent formation of cell syncytia. Infection leads to alterations in cell morphology and impairment of cell replication but not increased cell death. Infected cells showed decreased proliferation as measured by bromodeoxyuridine uptake, which was confirmed by blunting of the cell growth rate of infected cells compared with uninfected controls over time. The detailed analysis using novel, fluorescent-labeled HHV-6A or HHV-6B reagents demonstrated strong G₁/S phase inhibition in infected precursor cells. Cell cycle arrest in HHV-6-infected cells was associated with a profound decrease in the expression of the glial progenitor cell marker A2B5 and a corresponding increase in the oligodendrocyte differentiation marker GalC.

These data demonstrate for the first time that infection of primary human glial precursor cells with a neurologically relevant human herpesvirus causes profound alterations of critical precursor cell properties. In light of recent observations that repair of CNS demyelination is dependent on the generation of mature oligodendrocytes from the glial precursor cell pool, these findings may have broad implications for both the ineffective repair seen in demyelinating diseases and the disruption of normal glial maturation.

Key words: glial precursors; HHV-6; cell cycle; proliferation; differentiation; human

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Received Dec 18, 2003; revised March 18, 2004; accepted April 10, 2004.

This article has been cited by other articles:

				D. Donati, E. Martinelli, R. Cassiani-Ingoni, J. Ahlqvist, J. Hou, E. O. Major, and S. Jacobson Variant-Specific Tropism of Human Herpesvirus 6 in Human Astrocytes J. Virol., August 1, 2005; 79(15): 9439 - 9448. [Abstract] [Full Text] [PDF]

				M. L. Opsahl and P. G. E. Kennedy Early and late HHV-6 gene transcripts in multiple sclerosis lesions and normal appearing white matter Brain, March 1, 2005; 128(3): 516 - 527. [Abstract] [Full Text] [PDF]

				L. De Bolle, L. Naesens, and E. De Clercq Update on Human Herpesvirus 6 Biology, Clinical Features, and Therapy Clin. Microbiol. Rev., January 1, 2005; 18(1): 217 - 245. [Abstract] [Full Text] [PDF]

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